Cyclization for preparing halo-cephems

The invention provides a process for preparing an allenyl .beta.-lactam of formula (4), by reacting the hydroxyl group of a .beta.-lactam of formula (1) with a reactive derivative of sulfonic acid of formula (2) to convert the compound of formula (1) to a .beta.-lactam of formula (3), thereafter reacting the resulting .beta.-lactam with a basic anion exchange resin of the type having a tertiary organic base fixed to the resin and isolating the allenyl .beta.-lactam of formula (4) with stability and high purity in a high yield.The invention also provides a process for preparing an allenyl .beta.-lactam of formula (4), by reacting the hydroxyl group of a .beta.-lactam compound of formula (1) with a reactive derivative of sulfonic acid of formula (2) to convert the compound of the formula (1) to a .beta.-lactam compound of formula (3), thereafter reacting the resulting .beta.-lactam of formula (3) with a tertiary organic base to convert the compound (3) to the allenyl .beta.-lactam of formula (4), thereafter causing two kinds of ion exchange resins, i.e., an acidic cation exchange resin and a basic anion exchange resin, to alternately or simultaneously act on the lactam of formula (4) and isolating the allenyl .beta.-lactam of formula (4).Further, the invention provides a process for preparing a 3-halogenated cephem of formula (6), characterized by causing a halogenating reagent to act on an allenyl .beta.-lactam of formula (4) in the presence of a sulfinate ion or thiolate ion capturing agent to obtain the 3-halogenated cephem.

Skip to:  ·  Claims  ·  References Cited  · Patent History  ·  Patent History

Claims

1. A process for preparing a 3-halogenated cephem derivative represented by the formula (6), characterized by causing a halogenating reagent to act on an allenyl.beta.-lactam compound represented by the formula (4) in the presence of a sulfinate ion or thiolate ion capturing agent selected from the group consisting of trimethylsilyl halide, 0, N-bistrimethylsilylacetamide, bistrimethylsilylurea, hexamethyldisilazane, hexamethylsilylacetamide, lower alkyl acid halide, lower alkyl carbonic acid halide, diacid halide, lower alkyl acid anhydride, sulfonyl halide, sulfonic anhydride and aluminum halide, wherein said diacid halide is at least one of oxalyl chloride, tartaryl dichloride, succinyl dichloride and malonyl dichloride and said sulfonyl halide is selected from the group consisting of lower alkylsulfonyl chloride, arylsulfonyl chloride and halogenosulfonyl chloride, to obtain the 3-halogenated cephem derivative ##STR12## wherein R.sup.1 is a hydrogen atom, amino or protected amino, R.sup.2 is a hydrogen atom, halogen atom, lower alkoxyl formyl, acetyl, propionyl, butyryl, isobutyryl, or lower alkyl having hydroxyl or protected hydroxyl as a substituent, R.sup.3 is a hydrogen atom or carboxylic acid protecting group, R.sup.4 is an aromatic group which may have a substituent, or nitrogen-containing aromatic heterocyclic group which may have a substituent, wherein said substituent is selected from the group consisting of halogen atoms, straight-chain or branched C.sub.1-4 alkoxyl group, straight-chain or branched C.sub.1-4 alkylthio groups, straight-chain or branched C.sub.1-4 alkylsulfonyloxy groups, aromatic sulfonyloxy or methyl-substituted aromatic sulfonyloxy, straight-chain or branched C.sub.1-4 alkyl groups, amino, amino which has as a substituent one or two straight-chain or branched C.sub.1-4 alkyl groups, hydroxyl, acyloxy group represented by R'COO-- wherein R' is phenyl, tolyl, or straight-chain or branched C.sub.1-4 alkyl group, acyl group represented by R'CO-- wherein R' is as defined above, nitro, cyano, and phenyl, and n is 0 to 2, X is a halogen atom.

2. A process as defined in claim 1 wherein the acid halide is lower alkyl acid halide or bivalent acid halide selected from the group consisting of oxalyl chloride, tartaryl dichloride, succinyl dichloride, and malonyl dichloride.

3. A process as defined in claim 1 wherein the acid anhydride is lower alkyl acid anhydride selected from the group consisting of acetic anhydride, trifluoroacetic anhydride, succinic anhydride and malonic anhydride.

4. A process as defined in claim 1 wherein the sulfonic anhydride is lower alkylsulfonic anhydride, arylsulfonic anhydride or halogenosulfonic anhydride.

5. A process as defined in claim 1 wherein the halogenating reagent is aluminum halide, silyl halide, halogen salt of alkali metal and alkaline earth metal or a quaternary ammonium halide selected from the group consisting of ammonium chloride, triethylamine hydrochloride, tetra-n-butylammonium chloride, triethylbenzylammonium bromide and tetrabenzylammonium halide.

6. A process as defined in claim 1 wherein the aromatic sulfonyloxy is toluenesulfonyloxy.

7. A process as defined in claim 5 wherein the silyl halide is trimethylsilyl halide.

8. A process as defined in claim 1 wherein a silyl halide or aluminum halide is both the sulfinate ion or thiolate ion capturing agent and the halogenating reagent.

9. A process as defined in claim 8 wherein the silyl halide is trimethylsilyl halide.

Referenced Cited
U.S. Patent Documents
5162524 November 10, 1992 Farina
5204458 April 20, 1993 Torii
Foreign Patent Documents
4-282387 October 1992 JPX
616685 April 1980 CHX
Other references
  • Tanaka et al, Nippon Kaga Kukai #61, Spring Annual Meeting 1991, Section C 9, #46, p. 1832, with Translation. Tanaka, Syn Lett 1991, p. 888. Kukolja, J. Org Chem 41, 2276 (1976). Abstract for JP 4-282387 (1992).
Patent History
Patent number: 5929233
Type: Grant
Filed: Nov 6, 1996
Date of Patent: Jul 27, 1999
Assignee: Otsuka Kagaku Kabushiki Kaisha (Osaka-Fu)
Inventors: Sigeru Torii (Okayama-ken), Hideo Tanaka (Okayama-ken), Michio Sasaoka (Tokushima), Yutaka Kameyama (Tokushima), Isao Wada (Tokushima), Yasuhisa Amano (Tokushima)
Primary Examiner: Mark L. Berch
Law Firm: Nikaido Marmelstein Murray & Oram LLP
Application Number: 8/732,445